STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane

As the sole Ca2+ entry mechanism in a variety of non-excitable cells, store-operated calcium (SOC) influx is important in Ca2+ signalling and many other cellular processes. A calcium-release-activated calcium (CRAC) channel in T lymphocytes is the best-characterized SOC influx channel and is essential to the immune response, sustained activity of CRAC channels being required for gene expression and proliferation. The molecular identity and the gating mechanism of SOC and CRAC channels have remained elusive. Previously we identified Stim and the mammalian homologue STIM1 as essential components of CRAC channel activation in Drosophila S2 cells and human T lymphocytes. Here we show that the expression of EF-hand mutants of Stim or STIM1 activates CRAC channels constitutively without changing Ca2+ store content. By immunofluorescence, EM localization and surface biotinylation we show that STIM1 migrates from endoplasmic-reticulum-like sites to the plasma membrane upon depletion of the Ca2+ store. We propose that STIM1 functions as the missing link between Ca2+ store depletion and SOC influx, serving as a Ca2+ sensor that translocates upon store depletion to the plasma membrane to activate CRAC channels.     

Discovery of the short gamma-ray burst GRB 050709

Gamma-ray bursts (GRBs) fall into two classes: short-hard and long-soft bursts. The latter are now known to have X-ray and optical afterglows, to occur at cosmological distances in star-forming galaxies, and to be associated with the explosion of massive stars. In contrast, the distance scale, the energy scale and the progenitors of the short bursts have remained a mystery. Here we report the discovery of a short-hard burst whose accurate localization has led to follow-up observations that have identified the X-ray afterglow and (for the first time) the optical afterglow of a short-hard burst; this in turn led to the identification of the host galaxy of the burst as a late-type galaxy at z = 0.16 (ref. 10). These results show that at least some short-hard bursts occur at cosmological distances in the outskirts of galaxies, and are likely to be caused by the merging of compact binaries.     

Hypothalamic regulation of sleep and circadian rhythms

A series of findings over the past decade has begun to identify the brain circuitry and neurotransmitters that regulate our daily cycles of sleep and wakefulness. The latter depends on a network of cell groups that activate the thalamus and the cerebral cortex. A key switch in the hypothalamus shuts off this arousal system during sleep. Other hypothalamic neurons stabilize the switch, and their absence results in inappropriate switching of behavioural states, such as occurs in narcolepsy. These findings explain how various drugs affect sleep and wakefulness, and provide the basis for a wide range of environmental influences to shape wake-sleep cycles into the optimal pattern for survival.     

Foreshock sequences and short-term earthquake predictability on East Pacific Rise transform faults

East Pacific Rise transform faults are characterized by high slip rates (more than ten centimetres a year), predominantly aseismic slip and maximum earthquake magnitudes of about 6.5. Using recordings from a hydroacoustic array deployed by the National Oceanic and Atmospheric Administration, we show here that East Pacific Rise transform faults also have a low number of aftershocks and high foreshock rates compared to continental strike-slip faults. The high ratio of foreshocks to aftershocks implies that such transform-fault seismicity cannot be explained by seismic triggering models in which there is no fundamental distinction between foreshocks, mainshocks and aftershocks. The foreshock sequences on East Pacific Rise transform faults can be used to predict (retrospectively) earthquakes of magnitude 5.4 or greater, in narrow spatial and temporal windows and with a high probability gain. The predictability of such transform earthquakes is consistent with a model in which slow slip transients trigger earthquakes, enrich their low-frequency radiation and accommodate much of the aseismic plate motion.     

Differentiation of the asteroid Ceres as revealed by its shape

The accretion of bodies in the asteroid belt was halted nearly 4.6 billion years ago by the gravitational influence of the newly formed giant planet Jupiter. The asteroid belt therefore preserves a record of both this earliest epoch of Solar System formation and variation of conditions within the solar nebula. Spectral features in reflected sunlight indicate that some asteroids have experienced sufficient thermal evolution to differentiate into layered structures. The second most massive asteroid--4 Vesta--has differentiated to a crust, mantle and core. 1 Ceres, the largest and most massive asteroid, has in contrast been presumed to be homogeneous, in part because of its low density, low albedo and relatively featureless visible reflectance spectrum, similar to carbonaceous meteorites that have suffered minimal thermal processing. Here we show that Ceres has a shape and smoothness indicative of a gravitationally relaxed object. Its shape is significantly less flattened than that expected for a homogeneous object, but is consistent with a central mass concentration indicative of differentiation. Possible interior configurations include water-ice-rich mantles over a rocky core.     

Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse

Vacuolar-vesicular protein sorting (Vps) factors are involved in vesicular trafficking in eukaryotic cells. We identified the missense mutation L967Q in Vps54 in the wobbler mouse, an animal model of amyotrophic lateral sclerosis, and also characterized a lethal allele, Vps54(beta-geo). Motoneuron survival and spermiogenesis are severely compromised in the wobbler mouse, indicating that Vps54 has an essential role in these processes.     

Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans

The functional interaction of BAFF and APRIL with TNF receptor superfamily members BAFFR, TACI and BCMA is crucial for development and maintenance of humoral immunity in mice and humans. Using a candidate gene approach, we identified homozygous and heterozygous mutations in TNFRSF13B, encoding TACI, in 13 individuals with common variable immunodeficiency. Homozygosity with respect to mutations causing the amino acid substitutions S144X and C104R abrogated APRIL binding and resulted in loss of TACI function, as evidenced by impaired proliferative response to IgM-APRIL costimulation and defective class switch recombination induced by IL-10 and APRIL or BAFF. Family members heterozygous with respect to the C104R mutation and individuals with sporadic common variable immunodeficiency who were heterozygous with respect to the amino acid substitutions A181E, S194X and R202H had humoral immunodeficiency. Although signs of autoimmunity and lymphoproliferation are evident, the human phenotype differs from that of the Tnfrsf13b-/- mouse model.     

Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development

We identified homozygous truncating mutations in HOXA1 in three genetically isolated human populations. The resulting phenotype includes horizontal gaze abnormalities, deafness, facial weakness, hypoventilation, vascular malformations of the internal carotid arteries and cardiac outflow tract, mental retardation and autism spectrum disorder. This is the first report to our knowledge of viable homozygous truncating mutations in any human HOX gene and of a mendelian disorder resulting from mutations in a human HOX gene critical for development of the central nervous system.